Process for the synthesis of a-nor-seco compounds with sterane skeleton

ABSTRACT

The invention relates to a new process for the synthesis of 17β-hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-3-acid derivatives of formula (I)                    
     wherein the meaning of Z is carboxyl or formyl group and 
     to the new secoindoxylidene carboxylic acid derivatives of formula (II)                    
     wherein R 1  and R 2  independently are C 1 -C 4  alkyl or alkoxy group, hydrogen or halogen atom—which are intermediates for preparing the compounds of formula (I). 
     The 17β-hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-3-acid derivatives of formula (I) are intermediates in the synthesis of oxandrolon (17β-hydroxy-17α-methyl-2-oxa-5α-androstane-3-one), which is used as anabolic in therapy.

The invention relates to a new process for the synthesis of17β-hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-3-acid derivativesof formula (I)

wherein the meaning of Z is carboxyl or formyl group and

to the new secoindoxylidene carboxylic acid derivatives of formula (II)

wherein R¹ and R² independently are C₁-C₄ alkyl or alkoxy group,hydrogen or halogen atom—which are intermediates for preparing thecompounds of formula (I).

The 17β-hydroxy-17α-methyl-1,3 -seco-2-nor-5α-androstane-3-acidderivatives of formula (I) are intermediates in the synthesis ofoxandrolon (17β-hydroxy-17α-methyl-2-oxa-5α-androstane-3-one), which isused as anabolic in therapy. The oxandrolone is used in pediatrics andfor mitigation of loss of weight developing as a consequence ofinfections. traumas and surgical intervention. Recently the therapeuticuse was extended to the improvement of the condition of AIDS patients.

Although the 17β-hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-3-acidderivative of formula (I). wherein the meaning of Z is carboxyl group.is described in the literature [J. Steroid Biochem. Molec. Biol. 42(2).229-242 (1992)] as the metabolite of oxymethalone(17β-hydroxy-2-hydroxymethylene-17α-methyl-5α-androstane-3-one) and itsstructure was proved by GC-MS method via a derivative of it. itssynthesis and physical properties are not known.

The secoindoxylidene carboxylic acid type compounds of formula (II) arenew.

The 17β-hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-3-acidderivative of formula (I), wherein the meaning of Z is formyl group. isknown, its synthesis is described in several patents, i.e. the U.S. Pat.Nos. 3.101,349, 3,128,283 and 3,155,684, the German patent No. 1.171.425and the French patent No. M1697. These patents describe the oxidation of17β-hydroxy-17α-methyl-5α-androst-1-ene-3-one with lead tetraacetate inthe presence of osmium tetroxide, when17β-hydroxy-17α-methyl-1-oxo-1,3-seco-2-nor-5α-androstane-3-acid isobtained. The descriptions do not give yields. The use of leadtetraacetate and especially the osmium tetroxide is extremely dangerousfor health and not environmental friendly. An other difficulty is thatthe synthesis of the starting material, the17β-hydroxy-17α-methyl-5α-androst-1-ene-3-one, can be carried out onlyin low yield by bromination of17β-hydroxy-17α-methyl-5α-androstane-3-one and subsequent hydrogenbromide elimination. This procedure is described i.e. in the U.S. Pat.No. 3128,283. According to the U.S. Pat. No. 3.109,016 the oxidation ofthe above mentioned starting material is carried out by ozone in carbontetrachloride at −20° C. to yield the mixed anhydride of17β-hydroxy-17α-methyl-1-oxo-1,3-seco-2-nor-5α-androstane-3-acid formedwith formic acid. The oxidation was also carried out in dichloromethanein the presence of methanol to yield the methyl ester of the secocompound. The procedure does not give yields. As the use of carbontetrachloride is restricted because of its harmful effect to health, thesynthesis can not be used on industrial scale.

As can be seen from the state of arts despite the fact that there is aneed for the compounds of formula (I), there is no such procedure forthe synthesis of them. which can be carried out on industrial scale ingood yield and without using dangerous reagents.

Surprisingly it was found, that the17β-hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-3-acid derivativesof formula (I), known only as metabolites or intermediates, can besynthesized from 17β-hydroxy-17α-methyl-5α-androstane-3-one of formula(III)

known as mestanolone [Helv. Chim: Acta, 30(3), 867-878, (1947)]—by anindustrially applicable method according to our invention as follows:

The 17β-hydroxy-17α-methyl-5α-androstane-3-one of formula (III) isreacted with an aromatic nitro-aldehyde of formula (IV)

wherein R¹ and R² independently are C₁-C₄ alkyl or alkoxy group,hydrogen or halogen atom—in a C₁-C₄ alcohol in the presence of aqueousalkali metal hydroxide solution,

the obtained secoindoxylidene carboxylic acid derivative of formula (II)

wherein the meaning of R¹ and R² as defined above—is separated from thereaction mixture after acidifying in given case is recrystallized from aC₁-C₄ alcohol or C₃-C₅ ketone. and oxidized using

i) for the synthesis of17β-hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-3-acid derivative offormula (I), wherein Z is carboxyl group, at 15-40° C. 2.5-5 molequivalent, or

ii) for the synthesis of17β-hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-3-acid derivative offormula (I), wherein Z is formyl group, at 15-30° C. 1-1.5 molequivalent alkali metal permanganate in a mixture of C₁-C₅ alcohol orC₃-C₆ ketone and aqueous alkali metal hydroxide.

The reaction of mestanolone of formula (III) and aromatic nitro-aldehydeof formula (IV) is preferably carried out in methanol as C₁-C₄ alcoholin the presence of potassium hydroxide. The mestanolone is preferablysuspended in the mixture of the alcohol type solvent and the aqueousalkali metal hydroxide and the aromatic nitro-aldehyde of formula (IV)in alcoholic solution is added to the reaction. The addition can becarried out between 0° C. and the reflux temperature of the reactionmixture. The completion time of the reaction depends on the temperature.

After completion of the reaction the mixture was acidified with adiluted inorganic acid till pH=0-2.5. diluted with water, theprecipitated yellow crystals were filtered off, washed with aqueousalcohol and dried. The obtained secoindoxylidene carboxylic acid offormula (II), the substance content of which is 80-95%, isrecrystallized in given case from a C₁-C₄ alcohol or C₃-C₅ ketone.

The recrystallized or the crude secoindoxylidene carboxylic acid offormula (II) is dissolved in a mixture of C₁-C₅ alcohol or C₃-C₆ ketone,water and aqueous alkali metal hydroxide solution (pH=10-14) and for thesynthesis of 17β-hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-3-acidderivative of formula (I), wherein Z is carboxyl group, 2.5-5 molequivalent of alkali metal permanganate in aqueous solution is added tothe reaction at 15-40° C. The required temperature of 15-40° C. is keptwith cooling. As the reaction proceeds the mixture turns brown. due tothe precipitation of the manganese dioxide. After addition of thereagent the pH is checked and in case of deviation it is adjusted to therequired value by addition of further alkali metal hydroxide solution.After completion of the reaction the precipitated manganese dioxide isfiltered off or is dissolved with the addition of a reductive agent.i.e. sodium sulfite. the pH of the solution is adjusted to 5.5-6.5 andconcentrated. The possible impurities precipitated from the concentratedsolution are filtered off, the pH of the filtrate (which contains thedesired product) is adjusted to 0-2.5 with addition of acid. Theprecipitated product is filtered off, washed with water and dried. Thecrude product is purified be suspending and stirring it in a halogenatedalkan or in a mixture of a halogenated alkan and a ketone or in a ketonetype solvent and subsequent filtration or recrystallization from aketone type solvent.

If the above mentioned oxidation step is carried out the following way,instead of 17β-hydroxy- 17α-methyl-1,3-seco-2-nor-5α-androstane-3-acidderivative of formula (1), wherein Z is carboxyl group, the 17β-hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-3-acid derivative of formula(I), wherein Z is formyl group, is obtained. The reaction is carried outthe same way as in the synthesis of17β-hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-3-acid derivative offormula (I), wherein Z is carboxyl group, with the difference that thetemperature of the oxidation is 15-30° C. instead of 15-40° C. and 1-1.5mol equivalent of alkali metal permanganate is used instead of 2.5-5 molequivalent. The crude product is purified by recrystallization fromacetonitrile or from a ketone type solvent.

The oxidative cleavage of the C₁-C₂ double bond of secoindoxylidenecarboxylic acid derivatives of formula (II) is preferably carried out inacetone, ethanol or tertiary-butanol using sodium hydroxide as base.Both oxidation reactions are preferably carried out at 20-30° C.

The procedure according to the invention is illustrated in detail by thefollowing not limiting examples.

EXAMPLE 117β-Hydroxy-17α-methyl-1-(1,3-dihydro-3-oxo-2H-indol-2-ylidene)-1,3-seco-2-nor-5α-androstane-3-acid

27.6 g (490 mmol) of potassium hydroxide in 60 cm³ of water is added to1040 cm³ of methanol, then 50 g (164.2 mmol) of mestanolone is suspendedin the so obtained solution. 25 g (165.4 mmol) of 2-nitro-benzaldehydein 210 cm³ of methanol is added to the reaction mixture over a period of15 min. keeping the temperature at 25-30° C. with cooling. After theaddition of the reagent the starting material slowly dissolves and thecolour of the reaction mixture turns yellow. The mixture is stirred at20-30° C. for 3 h. then checked by thin layer chromatography. Aftercompletion of the reaction it is cooled to 10-15° C. and 200 cm³ (548.5mmol) of 10% hydrochloric acid was added over a period of 15 min keepingthe temperature below 20° C. During the addition of the hydrochloricacid the product starts to precipitate. Then 2500 cm³ of water is addedto the reaction mixture and it is stirred for 3.0 min. The precipitatedyellow crystals are filtered off. washed with water and dried at 50° C.till the weight was constant to yield 72.6 g, (96%. calculated for waterfree compound) of crude title compound. Alp: 170-190° C. Water content:5%.

70 g (66.5 g of water free compound) of the above crude product isrecrystallized from 4760 cm³ of methanol to yield 59.36 g (89.3%,calculated for water free starting material) of crystalline product. Mp:184-190° C. [α]_(D) ²⁵: +105.4° (c=1, acetone).

EXAMPLE 217β-Hydroxy-17α-methyl-1-(1,3-dihydro-3-oxo-2H-indol-2-ylidene)-1,3-seco-2-nor-5α-androstane-3-acid

332 g (5.92 mol) of potassium hydroxide in 730 cm³ of water is added to9.4 dm³ of methanol, then 600 g (1.97 mol) of mestanolone is suspendedin the so obtained solution. 300 g (1.98 mol) of 2-nitro-benzaldehyde in2.4 dm³ of methanol is added to the reaction mixture over a period of 10min. After the addition of the reagent the starting material slowlydissolves and the colour of the reaction mixture turns yellow. Themixture is refluxed for 1 h, then checked by thin layer chromatography.After completion of the reaction it is cooled to 15° C. and 2.6 dm³ of10% sulfuric acid is added over a period of 15-20min keeping thetemperature below 20° C. Then 24 dm³ of water is added to the reactionmixture and it is stirred for 30 min (pH=2). The precipitated yellowcrystals are filtered off, washed with a 3:1 mixture of water andmethanol and dried at 50° C. till the weight was constant to yield 902.5g (95.2%. calculated for water free compound) of crude title compound.Mp: 178-190° C. Water content: 5.3%.

EXAMPLE 317β-Hydroxy-17α-methyl-1-(5-chloro-1,3-dihydro-3-oxo-2H-indol-2-ylidene)-1,3-seco-2-nor-5α-androstane-3-acid

1.6 g (28.5 mmol) of potassium hydroxide is dissolved in a mixture of 4cm³ of water and 45 cm³ of methanol, then 3 g (9.85 mmol) of mestanoloneis added. 2.3 g (10.5 mmol) of 5-chloro-2-nitro-benzaldehyde (technicalquality, about 85%) in 25 cm³ of methanol is added to the basic reactionmixture. The mixture is stirred for 3 h. then checked by thin layerchromatography. After completion of the reaction it is cooled to 10-15°C. and 12 cm³ of 10% hydrochloric acid is added, then it is diluted with100 cm³ of water. After stirring for 20 min, the precipitated crystalsare filtered off, washed with 10 cm³ of water and dried at 50° C. Theobtained 4.8 g of crude product is crystallized from a mixture ofdichloromethane/acetonitril to yield 3.1 g (66.7%) of the titlecompound. Mp: 215-217° C. (decomposes).

EXAMPLE 4 17β-Hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-1,3-diacid

5 g (11.4 mmol) of crude17β-hydroxy-17α-methyl-1-(1,3-dihydro-3-oxo-2H-indol-2-ylidene)-1,3-seco-2-nor-5α-androstane-3-acid,obtained in Example 2 is dissolved in 40 cm³ of aceton and 0.8 g (20mmol) of sodium hydroxide in 40 cm³ of water is added. 2.7 g (17.1 mmol.1.5 equivalent) of potassium permanganate in 45 cm³ of water is added tothe reaction mixture over a period of 30 min. keeping the temperature at20-30° C. After stirring for 15 min, the precipitated manganese dioxideis filtered off and washed with 40 cm³ of a 1:3 mixture ofacetone-water. The filtrate is neutralized with 5 cm³ of 10% sulfuricacid is (pH˜6-7), then the acetone is evaporated at diminished pressure.The residue is cooled to 15-20° C. and acidified with 12 cm³ of 10%sulfuric acid (pH˜2). The crystalline solution is stirred for 20 min.then filtered, washed with water and dried at 50° C. till the weight isconstant to yield 1.9 g (51.6%) of the title compound. Mp: 166-173° C.

EXAMPLE 5 17β-Hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-1,3-diacid

5 g (11.4 mmol) of crude17β-hydroxy-17α-methyl-1-(1,3-dihydro-3-oxo-2H-indol-2-ylidene)-1,3-seco-2-nor-5α-androstane-3-acid,obtained in Example 2, is added to a mixture of 0.8 g (20 mmol) ofsodium hydroxide in 40 cm³ of water and 50 cm³ of ethanol. 5.4 g (34.2mmol, 3.0 equivalent) of potassium permanganate in 90 cm³ of water isadded to the reaction mixture over a period of 30 min, keeping thetemperature at 20-30° C. After stirring for 15 min, the precipitatedmanganese dioxide is filtered off and washed with 40 cm³ of a 1:3mixture of ethanol-water. The filtrate is neutralized with 5 cm³ of 10%sulfuric acid is (pH˜6-7), then the ethanol is evaporated at diminishedpressure. The residue is cooled to 15-20° C. and acidified with 12 cm³of 10% sulfuric acid (pH˜2). The crystalline solution is stirred for 20min. then filtered, washed with water and dried at 50° C. till theweight is constant to yield 2.5 g (64.6%) of crude title compound. Mp:177-190° C.

EXAMPLE 6 17β-Hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-1,3-diacid

5 g (11.4 mmol) of crude17β-hydroxy-17α-methyl-1-(1,3-dihydro-3-oxo-2H-indol-2-ylidene)-1,3-seco-2-nor-5α-androstane-3-acid,obtained in Example 2. is dissolved in 40 cm³ of acetone and 0.8 g (20mmol) of sodium hydroxide in 40 cm³ of water is added. 5.4 g (34.2 mmol.3.0 equivalent) of potassium permanganate in 90 cm³ of water is added tothe reaction mixture over a period of 30 min. keeping the temperature at20-30° C. After stirring for 15 min. the precipitated manganese dioxideis filtered off and washed with 40 cm³ of a 1:3 mixture ofacetone-water. The filtrate is neutralized with 5 cm³ of 10% sulfuricacid is (pH˜6-7), then the acetone is evaporated at diminished pressure.The residue is cooled to 15-20° C. and acidified with 12 cm³ of 10%sulfuric acid (pH˜2). The crystalline solution is stirred for 20 min.then filtered, washed with water and dried at 50° C. till the weight isconstant to yield 2.7 g (69.8%) of crude title compound. Mp: 176-189° C.

EXAMPLE 7 17β-Hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-1,3-diacid

469.0 g of crude 17β-hydroxy-17α-methyl-1-(1,3-dihydro-3-oxo-2H-indol-2-ylidene)-1,3-seco-2-nor-5α-androstane-3-acid,obtained in Example 2, is added to a stirred mixture of 60.0 g (1.5 mol)of sodium hydroxide in 3.0 dm³ of water and 6.5 dm³ of tertiary-butanol.After dissolving the starting material the pH of the solution is checked(pH=12-13). 433 g (2.74 mol) of potassium permanganate in 7.2 dm³ ofwater is added to the reaction mixture over a period of 2 h. keeping thetemperature at 20-30° C. with cooling. During the addition of thereagent the reaction mixture turns dark brown and manganese dioxideprecipitates. After addition of two third of the starting material 400cm³ of 10% sodium hydroxide is added to the reaction mixture and afterstirring for 5 min. the pH is checked (pH=12), then the addition of thereagent is continued. After the addition the reaction mixture is stirredfor 30 min at 20-30° C. Then the reaction mixture is filtered and themanganese dioxide is washed with 4.0 dm³ of a 1:3 mixture oftertiary-butanol-water. The filtrate is neutralized with 520 cm³ of 10%sulfuric acid is (pH˜6-7), then the tertiary-butanol is evaporated atdiminished pressure. The residue is cooled to 18-20° C. and after 20 minstirring the precipitated crystals (the by-products of the previous andthe present reaction) are filtered off and washed with 200 cm³ of water.The filtrate is acidified with 1300 cm³ of 10% sulfuric acid (pH˜2) at20-25° C. The crystalline solution is stirred for 15 min. then filtered,washed with water and dried at 50° C. till the weight is constant toyield 301 g (83.0%) of crude title compound. Mp: 176-190° C.

EXAMPLE 8 17β-Hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-1,3-diacid

469 g of recrystallized17β-hydroxy-17α-methyl-1-(1,3-dihydro-3-oxo-2H-indol-2-ylidene)-1,3-seco-2-nor-5α-androstane-3-acidobtained in Example 1. is added to a stirred mixture of 60 g (1.50 mol)of sodium hydroxide in 3.0 dm³ of water and 6.5 dm³ of tertiary-butanol.After dissolving the starting material the pH of the solution is checked(pH=12-13). 433 g (2.74 mol) of potassium permanganate in 7.2 dm³ ofwater is added to the reaction mixture over a period of 2 h. keeping thetemperature at 20-30° C. with cooling. During the addition of thereagent the reaction mixture turns dark brown and manganese dioxideprecipitates. After addition of two third of the starting material 400cm³ of 10% sodium hydroxide is added to the reaction mixture and afterstirring for 5 min, the pH is checked (pH=12), then the addition of thereagent is continued. After the addition the reaction mixture is stirredfor 30 min at 20-30° C. Then the reaction mixture is filtered and themanganese dioxide is washed with 4.0 dm³ of a 1:3 mixture oftertiary-butanol-water. The filtrate is neutralized with 520 cm³ of 10%sulfuric acid is (pH=6), then the tertiary-butanol is evaporated atdiminished pressure. The residue is cooled to 18-20° C. and after 20 minstirring the precipitated crystals (the by-products of the previous andthe present reaction) are filtered off and washed with 200 cm³ of water.The filtrate is acidified with 1300 cm³ of 10% sulfuric acid (pH=2) at20-25° C. The crystalline solution is stirred for 15 min, then filtered,washed with water and dried at 50° C. till the weight is constant toyield 359 g (99.0%) of crude title compound. Mp: 178-190° C.

EXAMPLE 9 17β-Hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-1,3-diacid

326 g of the crude product obtained in Example 7 is added to mixture of2.6 dm³ of dichloromethane and 650 cm³ of acetone over a period of 20min and the obtained suspension is stirred for 3 h. then filtered.washed with a mixture of 400 cm³ of dichloromethane and 100 cm³ ofacetone and dried at 50° C. to yield 2 g (71%) of the title compound.Mp: 249-251° C. [α]_(D) ²⁵=−18.4° (c=1, methanol).

EXAMPLE 1017β-Hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-1,3-diacid

25 g of the crude product obtained in Example 7 is dissolved in 530 cm³of acetone at reflux temperature, treated with 1.0 g of charcoal.filtered, then the filtrate is concentrated to a volume of 60 cm³. Theconcentrated mixture is cooled to 10° C. and kept at this temperaturefor 2 h, then the precipitated crystalline product is filtered off,washed with 20 cm³ of cold acetone and dried to yield 20.1 g (80.4%) ofthe title compound. Mp 248-250° C.

EXAMPLE 11 17β-Hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-1,3-diacid

3 g (6.4 mmol) of17β-hydroxy-17α-methyl-1-(5-chloro-1,3-dihydro-3-oxo-2H-indol-2-ylidene)-1,3-seco-2-nor-5α-androstane-3-acid,obtained in Example 3. is added to a stirred mixture of 0.5 a (12.5mmol) of sodium hydroxide in 20 cm³ of water and 50 cm³ oftertiary-butanol. 3.0 g (19 mmol, 3.0 equivalent) of potassiumpermanganate in 50 cm³ of water is added to the reaction mixture over aperiod of 30 min. keeping the temperature at 20-30° C. After stirringfor 15 min the precipitated manganese dioxide is filtered and washedwith 30 cm³ of a 1:3 mixture of tertiary-butanol-water. The filtrate isneutralized with 3 cm³ of 10% sulfuric acid is (pH˜6-7), then thetertiary-butanol is evaporated at diminished pressure. The residue iscooled to 15-20° C. and acidified with 9 cm³ of 10% sulfuric acid(pH˜2). The crystalline solution is stirred for 20 min. then filtered,washed with water and dried at 50° C. till the weight is constant toyield 2.0 g (93.0%) of crude title compound. Mp: 178-190° C.

What we claim is:
 1. A secoindoxylidene carboxylic acid of the formula(II)

wherein R¹ and R² independently are C₁-C₄ alkyl or alkoxy group,hydrogen or halogen atom. 2.17β-hydroxy-17α-methyl-1-(1,3-dihydro-3-oxo-2H-indol-2-ylidene)-1,3-seco-2-nor-5α-androstane-3-acidas in claim
 1. 3.17β-hydroxy-17α-methyl-1-(5-chloro-1,3dihydro-3-oxo-2H-indol-2-ylidene)-1,3-seco-2-nor-5α-androstane-3-acidas claimed in claim
 1. 4. Process for the synthesis of a17β-hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-3-acid of formula(I)

wherein the meaning of Z is carboxyl or formyl group—characterized byreacting the 17β-hydroxy-17α-methyl-5α-androstane-3-one (mestanolone) offormula (III)

with an aromatic nitro-aldehyde of formula (IV)

wherein R¹ and R² independently are C₁-C₄ alkyl or alkoxy group,hydrogen or halogen atom—in a C₁-C₄ alcohol in the presence of aqueousalkali metal hydroxide solution, the obtained secoindoxylidenecarboxylic acid of formula (II)

wherein the meaning of R¹ and R² as defined above—is separated from thereaction mixture after acidifying, in given case is recrystallized froma C₁-C₄ alcohol or C₃-C₅ ketone and oxidized using i) for the synthesisof 17β-hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-3-acid derivativeof formula (I), wherein Z is carboxyl group, at 15-40° C. 2.5-5 molequivalent, or ii) for the synthesis of17β-hydroxy-17α-methyl-1,3-seco-2-nor-5α-androstane-3-acid of formula(I), wherein Z is formyl group, at 15-30° C., 1-1.5 mol equivalentalkali metal permanganate in a mixture of C₁-C₅ alcohol or C₃-C₆ ketoneand aqueous alkali metal hydroxide.
 5. The process in claim 4,characterized by reacting the17β-hydroxy-17α-methyl-methyl-5α-androstane-3-one of formula (III) andthe aromatic aldehyde of formula (IV)—wherein the meaning of R¹ and R²as defined above—in a mixture of methanol and aqueous potassiumhydroxide.
 6. The process in claim 4, characterized by using2-nitro-benzaldehyde as aromatic aldehyde of formula (IV).
 7. Theprocess in claim 4, characterized by using 5-chloro-2-nitro-benzaldehydeas aromatic aldehyde of formula (IV).
 8. The process in claim 4,characterized by carrying out the oxidation of secoindoxylidenecarboxylic acid of formula (II)—wherein the meaning of R¹ and R² asdefined in claim 4—in a mixture of acetone and aqueous sodium hydroxide.9. The process in claim 4, characterized by carrying out the oxidationof secoindoxylidene carboxylic acid of formula (II)—wherein the meaningof R¹ and R² as defined in claim 4—in a mixture of ethanol and aqueoussodium hydroxide.
 10. The process in claim 4, characterized by carryingout the oxidation of secoindoxylidene carboxylic acid of formula(II)—wherein the meaning of R¹ and R² as defined in claim 4—in a mixtureof tertiary-butanol and aqueous sodium hydroxide.
 11. The process inclaim 4, characterized by carrying out the oxidation of secoindoxylidenecarboxylic acid derivatives of formula (II)—wherein the meaning of R¹ land R² as defined in claim 4—with potassium permanganate.